The Energy Landscape Analysis Of Cancer Mutations In Protein Kinases

Authors

Anshuman Dixit, University of Kansas - Main Campus
Gennady M. Verkhivker, Chapman UniversityFollow

Document Type

Article

Publication Date

2011

Abstract

The growing interest in quantifying the molecular basis of protein kinase activation and allosteric regulation by cancer mutations has fueled computational studies of allosteric signaling in protein kinases. In the present study, we combined computer simulations and the energy landscape analysis of protein kinases to characterize the interplay between oncogenic mutations and locally frustrated sites as important catalysts of allostetric kinase activation. While structurally rigid kinase core constitutes a minimally frustrated hub of the catalytic domain, locally frustrated residue clusters, whose interaction networks are not energetically optimized, are prone to dynamic modulation and could enable allosteric conformational transitions. The results of this study have shown that the energy landscape effect of oncogenic mutations may be allosteric eliciting global changes in the spatial distribution of highly frustrated residues. We have found that mutation-induced allosteric signaling may involve a dynamic coupling between structurally rigid (minimally frustrated) and plastic (locally frustrated) clusters of residues. The presented study has demonstrated that activation cancer mutations may affect the thermodynamic equilibrium between kinase states by allosterically altering the distribution of locally frustrated sites and increasing the local frustration in the inactive form, while eliminating locally frustrated sites and restoring structural rigidity of the active form. The energy landsape analysis of protein kinases and the proposed role of locally frustrated sites in activation mechanisms may have useful implications for bioinformatics-based screening and detection of functional sites critical for allosteric regulation in complex biomolecular systems.

Comments

This article was originally published in PLoS ONE, volume 6, issue 10, in 2011. DOI: 10.1371/journal.pone.0026071

Recommended Citation

Dixit A, Verkhivker GM (2011) The Energy Landscape Analysis of Cancer Mutations in Protein Kinases. PLoS ONE 6(10): e26071. doi:10.1371/journal.pone.0026071

Peer Reviewed

1

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.